As the list of expressed human genes expands, a major scientific and medical challenge is to understand the molecular events that drive normal tissue morphogenesis and the progression of pathologic lesions in actual tissue. With refinements in PCR, microhybridization arrays and mutation screening, and proteomics, tissue biopsies can be analyzed for levels of hundreds or even thousands distinct macromolecules. Since complex tissues consist of multiple cells types biochemically and physically affected by surrounding cells and molecular environments, the task of analyzing critical gene expression patterns in development, normal function, and disease progression depends on the identification and extraction of specific cells from their complex tissue milieu. Previously we developed laser capture microdissection (LCM) to provide a microscope-based, user-directed method to procure pure populations of specified cells from specific microscopic regions of tissue sections for subsequent quantitative, multiplex molecular analysis. We have collaborated using our microdissection technologies on global analyses of gene expression using microarray hybridization of neural tissues and in spatial and temporal mapping of DNA repair processes. Using microdissection, we continue to explore critical gene expression changes that are associated with stages of cancer progression in a mouse model of induction and progression of plasmacytomas induced by chronic inflammation and in early cancer invasion. In the last year with NCI and CIT, we have developed a new rapid scanning technology capable of automatically, specifically microbonding onto a flexible thermoplastic tape those cells that are immunostained within a complex tissue section with very high rates (~50,000 cells scanned per sec) and resolution (~1micron). With further improvements in our new expression microdissection technique, we hope to greatly expand the utility of microdissection in research studies, particularly in proteomics and lipidomics, which require the combination of high resolution targeting and high speed that it provides. Sets of macromolecules found to be uniquely associated with a defined pathological lesion in clinical studies may serve diagnostic imaging markers in screening of populations at risk and for evaluating response to therapy designed to prevent progression. In the longer term, we are evaluating the potential role of our evolving expression microdissection technology both in clinical screening and response to early intervention designed to prevent progression.